Field of the Disclosure
This disclosure relates generally to novel prodrugs of vitamin D-related compounds. In particular, the disclosure includes 1-deoxy prohormones of active Vitamin D hormones, e.g. analogs of calcitriol, and 1-deoxy analogs of CYP24 inhibitors, pharmaceutical and diagnostic compositions containing them, and to their medical use, particularly as prodrugs in the treatment and/or prevention of diseases.
Brief Description of Related Technology
“Vitamin D” is a term that refers broadly to the organic substances named Vitamin D2, Vitamin D3, Vitamin D4, etc., and to their metabolites and hormonal forms that influence calcium and phosphorus homeostasis.
The most widely recognized forms of Vitamin D are Vitamin D2 (ergocalciferol) and Vitamin D3 (cholecalciferol). Vitamin D2 is produced in plants from ergosterol during sunlight exposure and is present, to a limited extent, in the human diet. Vitamin D3 is generated from 7-dehydrocholesterol in human skin during exposure to sunlight and also is found, to a greater extent than Vitamin D2, in the human diet, principally in dairy products (milk and butter), certain fish and fish oils, and egg yolk. Vitamin D supplements for human use consist of either Vitamin D2 or Vitamin D3.
Both Vitamin D2 and Vitamin D3 are metabolized into prohormones by one or more enzymes located in the liver. The involved enzymes are mitochondrial and microsomal cytochrome P450 (CYP) isoforms, including CYP27A1, CYP2R1, CYP3A4, CYP2J3 and possibly others. These enzymes metabolize Vitamin D2 into two prohormones known as 25-hydroxyvitamin D2 and 24(S)-hydroxyvitamin D2, and Vitamin D3 into a prohormone known as 25-hydroxyvitamin D3. The two 25-hydroxylated prohormones are more prominent in the blood, and can be collectively referred to as “25-hydroxyvitamin D.” Vitamin D2 and Vitamin D3 can be metabolized into their respective prohormones outside of the liver in certain epithelial cells, such as enterocytes, which contain the same (or similar) enzymes, but extrahepatic prohormone production probably contributes little to blood levels of 25-hydroxyvitamin D.
The rates of hepatic and extrahepatic production of the Vitamin D prohormones are not tightly regulated, and they vary mainly with intracellular concentrations of the precursors (Vitamin D2 and Vitamin D3). Higher concentrations of either precursor increase prohormone production, while lower concentrations decrease production. Hepatic production of prohormones is inhibited by high levels of 25-hydroxyvitamin D via a poorly understood mechanism apparently directed to prevention of excessive blood prohormone levels.
The Vitamin D prohormones are further metabolized in the kidneys into potent hormones by an enzyme known as CYP27B1 (or 25-hydroxyvitamin D3-1α-hydroxylase) located in the proximal kidney tubule. The prohormones 25-hydroxyvitamin D2 and 24(S)-hydroxyvitamin D2 are metabolized into hormones known as 1α,25-dihydroxyvitamin D2 and 1α,24(S)-dihydroxyvitamin D2. Likewise, 25-hydroxyvitamin D3 is metabolized into a hormone known as 1α,25-dihydroxyvitamin D3 (or calcitriol). These hormones are released by the kidneys into the blood for systemic delivery. The two 1α,25-dihydroxylated hormones, usually far more prominent in the blood than 1α,24(S)-dihydroxyvitamin D2, can be collectively referred to as “1,25-dihydroxyvitamin D.” Vitamin D prohormones can be metabolized into hormones outside of the kidneys in keratinocytes, lung epithelial cells, enterocytes, cells of the immune system (e.g., macrophages) and certain other cells containing CYP27B1 or similar enzymes, but such extrarenal hormone production is incapable of sustaining normal blood levels of 1,25-dihydroxyvitamin D in advanced chronic kidney disease (CKD).
Blood levels of 1,25-dihydroxyvitamin D are precisely regulated by a feedback mechanism which involves parathyroid hormone (PTH). The renal 1α-hydroxylase (or CYP27B1) is stimulated by PTH and inhibited by 1,25-dihydroxyvitamin D. When blood levels of 1,25-dihydroxyvitamin D fall, the parathyroid glands sense this change via intracellular Vitamin D receptors (VDR) and secrete PTH. The secreted PTH stimulates expression of renal CYP27B1 and, thereby, increases production of Vitamin D hormones. As blood concentrations of 1,25-dihydroxyvitamin D rise again, the parathyroid glands attenuate further PTH secretion. As blood PTH levels fall, renal production of Vitamin D hormones decreases. Rising blood levels of 1,25-dihydroxyvitamin D also directly inhibit further Vitamin D hormone production by CYP27B1.
PTH secretion can be abnormally suppressed in situations in which blood 1,25-dihydroxyvitamin D concentrations become excessively elevated, as can occur in certain disorders such as sarcoidosis or as a result of bolus doses of Vitamin D hormone replacement therapies. Oversuppression of PTH secretion can cause or exacerbate disturbances in calcium homeostasis. The parathyroid glands and the renal CYP27B1 are exquisitely sensitive to changes in blood concentrations of Vitamin D hormones so that serum 1,25-dihydroxyvitamin D is tightly controlled, fluctuating up or down by less than 20% during any 24-hour period. In contrast to renal production of Vitamin D hormones, extrarenal production is not under precise feedback control.
Blood levels of 1,25-dihydroxyvitamin D and substrate 25-hydroxyvitamin D prohormone, and regulation thereof, can also be affected by vitamin D hormone analogs, such as 19-nor-1,25 dihydroxyvitamin D2 and 22-oxacalcitriol, the prodrugs 1α-hydroxyvitamin D2 and 1α-hydroxyvitamin D2, 24-sulfoximine vitamin D3 compounds, oxime analogs of 1α,25-dihydroxyvitamin D3, and 25-SO2 substituted analogs of 1α,25-dihydroxyvitamin D3, as disclosed in U.S. Pat. No. 7,101,865, U.S. Pat. No. 6,982,258, and U.S. Patent Application No. 2004/0224930, respectively, which are hereby incorporated by reference.
The Vitamin D hormones have essential roles in human health which are mediated by the intracellular VDR. In particular, the Vitamin D hormones regulate blood calcium levels by controlling intestinal absorption of dietary calcium and reabsorption of calcium by the kidneys. Excessive hormone levels can lead to abnormally elevated urine calcium (hypercalciuria), blood calcium (hypercalcemia) and blood phosphorus (hyperphosphatemia). Vitamin D deficiency, on the other hand, is associated with secondary hyperparathyroidism, parathyroid gland hyperplasia, hypocalcemia, CKD, and metabolic bone diseases such as osteitis fibrosa cystica, osteomalacia, rickets, osteoporosis, and extraskeletal calcification. Further, Vitamin D hormones are required for the normal functioning of the musculoskeletal, immune and renin-angiotensin systems. Numerous other roles for Vitamin D hormones are being postulated and elucidated, based on the documented presence of intracellular VDR in nearly every human tissue. For example, vitamin D has been postulated to play a role in cellular differentiation and cancer, in regulation of the immune system (immune enhancing or immune suppressing effects, depending on the situation), atherosclerosis, growth and normal bone formation and metabolism. Vitamin D deficiency increases the risk of many common cancers, multiple sclerosis, rheumatoid arthritis, hypertension, cardiovascular heart disease, blood pressure, antifibrosis, red blood cell formation, hair growth, and type I diabetes.
The actions of Vitamin D hormones on specific tissues depend on the degree to which they bind to (or occupy) the intracellular VDR in those tissues. VDR binding increases as the intracellular concentrations of the hormones rise, and decreases as the intracellular concentrations fall. In all cells, intracellular concentrations of the Vitamin D hormones change in direct proportion to changes in blood hormone concentrations. In cells containing CYP27B1 (or similar enzymes), intracellular concentrations of the Vitamin D hormones also change in direct proportion to changes in blood and/or intracellular prohormone concentrations, as discussed above.
Vitamin D2, Vitamin D3 and their prohormonal forms have affinities for the VDR which are estimated to be at least 100-fold lower than those of the active Vitamin D hormones and do not effectively activate the receptor. As a consequence, physiological concentrations of these hormone precursors exert little, if any, biological actions without prior metabolism to active Vitamin D hormones. However, supraphysiological levels of these hormone precursors, especially the prohormones, in the range of 10 to 1,000 fold higher than normal, can sufficiently occupy the VDR and exert actions like the Vitamin D hormones.
Blood levels of Vitamin D2 and Vitamin D3 are normally present at stable concentrations in human blood, given a sustained, adequate supply of Vitamin D from sunlight exposure and an unsupplemented diet. Slight, if any, increases in blood Vitamin D levels occur after meals since unsupplemented diets have low Vitamin D content, even those containing foods fortified with Vitamin D. The Vitamin D content of the human diet is so low that the National Institutes of Health (NIH) cautions “it can be difficult to obtain enough Vitamin D from natural food sources” [NIH, Office of Dietary Supplements, Dietary Supplement Fact Sheet: Vitamin D (2005)]. Almost all human Vitamin D supply comes from fortified foods, exposure to sunlight or from dietary supplements, with the last source becoming increasingly important. Blood Vitamin D levels rise only gradually, if at all, after sunlight exposure since cutaneous 7-dehydrocholesterol is modified by UV radiation to pre-Vitamin D3 which undergoes thermal conversion in the skin to Vitamin D3 over a period of several days before circulating in the blood.
Blood Vitamin D hormone concentrations also remain generally constant through the day in healthy individuals, but can vary significantly over longer periods of time in response to seasonal changes in sunlight exposure or sustained alterations in Vitamin D intake. Marked differences in normal Vitamin D hormone levels are commonly observed between healthy individuals, with some individuals having stable concentrations as low as approximately 20 pg/mL and others as high as approximately 70 pg/mL. Due to this wide normal range, medical professionals have difficulty interpreting isolated laboratory determinations of serum total 1,25-dihydroxyvitamin D; a value of 25 pg/mL may represent a normal value for one individual or a relative deficiency in another.
Transiently low blood levels of 1,25-dihydroxyvitamin D stimulate the parathyroid glands to secrete PTH for brief periods ending when normal blood Vitamin D hormone levels are restored. In contrast, chronically low blood levels of 1,25-dihydroxyvitamin D continuously stimulate the parathyroid glands to secrete PTH, resulting in a disorder known as secondary hyperparathyroidism. Chronically low hormone levels also decrease intestinal calcium absorption, leading to reduced blood calcium concentrations (hypocalcemia) which further stimulate PTH secretion. Continuously stimulated parathyroid glands become increasingly hyperplastic and eventually develop resistance to regulation by vitamin D hormones. Without early detection and treatment, secondary hyperparathyroidism progressively increases in severity, causing debilitating metabolic bone diseases, including osteoporosis and renal osteodystrophy.
Chronically low blood levels of 1,25-dihydroxyvitamin D can develop when there is insufficient renal CYP27B1 to produce the required supply of Vitamin D hormones, a situation which can arise in late stage CKD. The activity of renal CYP27B1 declines as the Glomerular Filtration Rate (GFR) falls below approximately 60 ml/min/1.73 m2 due to the loss of functioning nephrons. In end-stage renal disease (ESRD), when the kidneys fail completely and hemodialysis is required for survival, renal CYP27B1 often becomes altogether absent. Any remaining CYP27B1 is greatly inhibited by elevated serum phosphorous (hyperphosphatemia) caused by inadequate renal excretion of dietary phosphorous. Recently, however, it has been demonstrated that in earlier stages of CKD, blood levels of 1,25-dihydroxyvitamin D can be low, even when CYP27B1 expression is normal. Without intending to be bound by any particular theory, it is possible that disease related expression of CYP24A1 in kidney may be responsible for the decreased vitamin D status in such patients. We have therefore developed compounds which can take advantage of the residual CYP27B to generate sufficient vitamin D hormone to control the symptoms of CKD.
Chronically low blood levels of 1,25-dihydroxyvitamin D also develop because of a deficiency of Vitamin D prohormones, since renal hormone production cannot proceed without the required precursors. Prohormone production declines markedly when cholecalciferol and ergocalciferol are in short supply, a condition often described by terms such as “Vitamin D insufficiency,” “Vitamin D deficiency,” or “hypovitaminosis D.” Therefore, measurement of 25-hydroxyvitamin D levels in blood has become the accepted method among healthcare professionals to monitor Vitamin D status. Recent studies have documented that the great majority of CKD patients have low blood levels of 25-hydroxyvitamin D, and that the prevalence of Vitamin D insufficiency and deficiency increases as CKD progresses.
The National Kidney Foundation (NKF) has recently focused the medical community's attention on the need for early detection and treatment of secondary hyperparathyroidism by publishing Kidney Disease Outcomes Quality Initiative (K/DOQI) Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease [Am. J. Kidney Dis. 42:S1-S202, 2003)]. The K/DOQI Guidelines identified the primary etiology of secondary hyperparathyroidism as chronically low blood levels of 1,25-dihydroxyvitamin D and recommended regular screening in CKD Stages 3 through 5 for elevated blood PTH levels relative to Stage-specific PTH target ranges. CKD Stage 3 was defined as moderately decreased kidney function (GFR of 30-59 mL/min/1.73 m2) with an intact PTH (iPTH) target range of 35-70 pg/mL; Stage 4 was defined as severely decreased kidney function (GFR of 15-29 mL/min/1.73 m2), with an iPTH target range of 70-110 pg/mL; and Stage 5 was defined as kidney failure (GFR of <15 mL/min/1.73 m2 or dialysis) with an iPTH target range of 150-300 pg/mL. In the event that screening revealed an iPTH value to be above the ranges targeted for CKD Stages 3 and 4, the Guidelines recommended a follow-up evaluation of serum total 25-hydroxyvitamin D to detect possible Vitamin D insufficiency or deficiency. If 25-hydroxyvitamin D levels below 30 ng/mL was observed, the recommended intervention was Vitamin D repletion therapy using orally administered ergocalciferol. If 25-hydroxyvitamin D levels above 30 ng/mL was observed, the recommended intervention was Vitamin D hormone replacement therapy using known oral or intravenous Vitamin D hormones or analogs.
The NKF K/DOQI Guidelines defined Vitamin D sufficiency as serum 25-hydroxyvitamin D levels ≧30 ng/mL. Recommended Vitamin D repletion therapy for patients with “Vitamin D insufficiency,” defined as serum 25-hydroxyvitamin D of 16-30 ng/mL, was 50,000 IU per month of oral Vitamin D2 for 6 months, given either in single monthly doses or in divided doses of approximately 1,600 IU per day. Recommended repletion therapy for patients with “Vitamin D deficiency” was more aggressive: for “mild” deficiency, defined as serum 25-hydroxyvitamin D of 5-15 ng/mL, the Guidelines recommended 50,000 IU per week of oral Vitamin D2 for 4 weeks, followed by 50,000 IU per month for another 5 months; for “severe” deficiency, defined as serum 25-hydroxyvitamin D below 5 ng/mL, the Guidelines recommended 50,000 IU/week of oral Vitamin D2 for 12 weeks, followed by 50,000 IU/month for another 3 months. Doses of 50,000 IU per week are approximately equivalent to 7,000 IU per day.
As previously described, Vitamin D hormone replacement therapy is used to treat or prevent vitamin D insufficiency or deficiency in patients. Activated Vitamin D, particularly 1α,25-dihydroxyvitamin D3 (calcitriol), is especially perceived as a valuable therapeutic agent to treat vitamin D insufficiency or deficiency, as well as for a wide range of maladies such as metabolic bone disease, osteoporosis, psoriasis, psoriatic arthritis, colon, prostate and breast cancer, and HIV infection.
